Journal of Cerebral Blood Flow and Metabolism最新文献

Functional Positron Emission Tomography (fPET) is an effective tool for studying dynamic processes in glucose metabolism and neurotransmitter action, providing insights into brain function and disease progression. However, optimizing signal processing to extract stimulation-specific information remains challenging. This study systematically evaluates state-of-the-art filtering techniques for fPET imaging. Forty healthy participants performed a cognitive task (Tetris®) during [¹⁸F]FDG PET/MR scans. Seven filtering techniques and multiple hyperparameters were tested: including 3D and 4D Gaussian smoothing, highly constrained backprojection (HYPR), iterative HYPR (IHYPR4D), MRI-Markov Random Field (MRI-MRF) filters, and dynamic/extended dynamic Non-Local Means (dNLM/edNLM). Filters were assessed based on test-retest reliability, task signal identifiability (temporal signal-to-noise ratio, tSNR), spatial task-based activation, and sample size calculations were assessed. Compared to 3D Gaussian smoothing, edNLM, dNLM, MRI-MRF L = 10, and IHYPR4D filters improved tSNR, while edNLM and HYPR enhanced test-retest reliability. Spatial task-based activation was enhanced by NLM filters and MRI-MRF approaches. The edNLM filter reduced the required sample size by 15.4%. Simulations supported these findings. This study highlights the strengths and limitations of fPET filtering techniques, emphasizing how hyperparamter adjustments affect outcome parameters. The edNLM filter shows promise with improved performance across all metrics, but filter selection should consider specific study objectives and resource constraints.

In the past decade, noble gases have emerged as highly promising neuroprotective agents. Previous studies have demonstrated the efficacy of argon neuroprotection in rodent models of cerebral ischemia. The objective of the present pre-clinical study was to confirm the neuroprotective effect of argon in a non-human primate model of endovascular ischemic stroke. Thirteen adult Macaca mulatta were subjected to a focal cerebral ischemia induced by a transient (90 min) middle cerebral artery occlusion (tMCAO). The monkeys were randomly allocated to a control group (n = 8) and an argon group (n = 5). Pre-mixed gas (40-60 oxygen-argon) was applied 30 min after the onset of tMCAO to 30 min after reperfusion. Infarct volumes were measured from the MRI scans conducted 1 hour and 1 month after the reperfusion. A clinical neurological assessment was performed 24 hours and 1 month after tMCAO. Our results show that Argon dramatically reduced ischemic core volume after ischemia compared to the control group with a long-lasting improvement of post-stroke infarct volume at 1 month. In addition, the neurological scale suggests a better prognosis in argon-treated animals without reaching the significance threshold. These pre-clinical results in gyrencephalic non-human primates support the potential use of this therapeutic approach for future clinical studies.

Optical coherence tomography angiography (OCT-A) retinal imaging enables in vivo visualization of the retinal microvasculature that is developmentally related to the brain and can offer insight on cerebrovascular health. We investigated retinal phenotypes and neuroimaging markers of small vessel disease (SVD) in individuals with obstructive sleep apnoea (OSA). We enrolled 44 participants (mean age 50.1 ± SD 9.1 years) and performed OCT-A imaging before and after continuous positive airway pressure (CPAP) therapy. Pre-treatment analyses using a generalized estimating equations model adjusted for relevant covariates, revealed perivascular spaces (PVS) volume in basal ganglia associated with greater foveal vessel density (fVD) (p-value < 0.001), and smaller foveal avascular zone area (p-value = 0.01), whereas PVS count in centrum semiovale associated with lower retinal vessel radius (p-value = 0.02) and higher vessel tortuosity (p-value = 0.01). A reduction in retinal vessel radius was also observed with increased OSA severity (p-value = 0.05). Post-treatment analyses showed greater CPAP usage was associated with a decrease in fVD (p-value = 0.02), and increased retinal vessel radius (p-value = 0.01). The findings demonstrate for the first time the potential use of OCT-A to monitor CPAP treatment and its possible impact on both retinal and brain vascular health.

While the associations of mid-life cardiovascular risk factors with late-life white matter lesions (WMH) and cognitive decline have been established, the role of cerebral haemodynamics is unclear. We investigated the relation of late-life (69-71 years) arterial spin labelling (ASL) MRI-derived cerebral blood flow (CBF) with life-course cardiovascular risk factors (36-71 years) and late-life white matter hyperintensity (WMH) load in 282 cognitively healthy participants (52.8% female). Late-life (69-71 years) high systolic (B = -0.15) and diastolic (B = -0.25) blood pressure, and mean arterial pressure (B = -0.25) were associated with low grey matter (GM) CBF (p < 0.03), and white matter CBF (B = -0.25; B = -0.15; B = -0.13, p < 0.03, respectively). The association between systolic blood pressure and GM CBF differed between sexes (male/female B = -0.15/0.02, p = 0.04). No associations were found with early- or mid-life cardiovascular risk factors. Furthermore, WMHs were associated with cerebral haemodynamics but not cardiovascular risk factors. These findings suggest that cerebral blood flow autoregulation is able to maintain stable global cerebral haemodynamics until later in life. Future studies are encouraged to investigate why cardiovascular risk factors have differential effects on haemodynamics and WMH, and their implications for cognitive decline.

A potential two-way passage of cells and substances between the brain and skull bone marrow may open for new insights into neurological disease. The arachnoid membrane was traditionally considered to restrict cells and larger molecules in CSF from entering the dura and bone marrow directly. However, new data on exchange between brain and skull bone marrow have recently emerged. Here, we conducted a systematic literature to answer the question: What is the current evidence regarding the movement of cells and molecules between the brain and skull bone marrow, spanning CSF and meninges? We excluded studies related to head or skull trauma, cranial fractures or defects, cancer invasion, CSF leakage, spontaneous intracranial hypotension, spinal dura mater, and studies solely focusing on meningeal lymphatic vessels or the passage of substances from CSF to meningeal lymphatic vessels. The review identified 16 studies that provide evidence of communication between the brain, meninges and skull bone marrow. Cells (such as B and T cells and neutrophils), bacteria, and substances (tracers, drug compounds) have been reported to pass between the brain and skull bone. However, most studies are performed in rodents, emphasizing the need for translation to humans.

Hypoxic-ischemic (HI) encephalopathy is a cerebrovascular injury caused by oxygen deprivation to the brain and remains a major cause of neonatal mortality and morbidity worldwide. Therapeutic hypothermia is the current standard of care but it does not provide complete neuroprotection. Our aim was to investigate the neuroprotective effect of oleuropein (Ole) in a neonatal (seven-day-old) mouse model of HI. Ole, a secoiridoid found in olive leaves, has previously shown to reduce damage against cerebral and other ischemia/reperfusion injuries. Here, we administered Ole as a pretreatment prior to HI induction at 20 or 100 mg/kg. A week after HI, Ole significantly reduced the infarct area and the histological damage as well as white matter injury, by preserving myelination, microglial activation and the astroglial reactive response. Twenty-four hours after HI, Ole reduced the overexpression of caspase-3 and the proinflammatory cytokines IL-6 and TNF-α. Moreover, using UPLC-MS/MS we found that maternal supplementation with Ole during pregnancy and/or lactation led to the accumulation of its metabolite hydroxytyrosol in the brains of the offspring. Overall, our results indicate that pretreatment with Ole confers neuroprotection and can prevent HI-induced brain damage by modulating apoptosis and neuroinflammation.

The study investigated the sensitivity of a novel MRI-based OEF mapping, quantitative susceptibility mapping plus quantitative blood oxygen level-dependent imaging (QSM+qBOLD or QQ), to physiological changes, particularly increased oxygen extraction fraction (OEF) by using hyperventilation as a vasoconstrictive stimulus. While QQ's sensitivity to decreased OEF during hypercapnia has been demonstrated, its sensitivity to increased OEF levels, crucial for cerebrovascular disorders like vascular dementia and Parkinson's disease, remains unexplored. In comparison with a previous QSM-based OEF, we evaluated QQ's sensitivity to high OEF values. MRI data were obtained from 11 healthy subjects during resting state (RS) and hyperventilation state (HV) using a 3 T MRI with a three-dimensional multi-echo gradient echo sequence (mGRE) and arterial spin labeling (ASL). Region of interest (ROI) analysis and paired t-tests were used to compare OEF, CMRO₂ and CBF between QQ and QSM. Similar to QSM, QQ showed higher OEF during HV compared to RS: in cortical gray matter, QQ-OEF and QSM-OEF was 36.4$\hspace{0.17em}\pm \hspace{0.17em}$4.7% and 35.3$\hspace{0.17em}\pm \hspace{0.17em}$12.5% at RS and 45.0$\hspace{0.17em}\pm \hspace{0.17em}$11.6% and 45.0$\hspace{0.17em}\pm \hspace{0.17em}$14.8% in HV, respectively. These findings demonstrate QQ's ability to detect physiological changes and suggest its potential in studying brain metabolism in neurological disorders.

This paper describes the preclinical validation of the radioligand [¹¹C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α_2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α_2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [³H]ORM-13070. BAY 292 bound to the same binding site as [³H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α_2CR. In non-human primates in vivo, [¹¹C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α_2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC₅₀ for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [¹¹C]ORM-13070 as a PET-radioligand for the study of α_2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.

Endovascular thrombectomy has a recanalization rate over 80%; however, approximately 50% of ischemic stroke patients still experience dependency or mortality. Recently, clinical trials demonstrated the benefits of administering neuroprotective agents prior to endovascular thrombectomy. Additionally, recent studies showed neuroprotective effects of mild hypercapnia in patients resuscitated after cardiac arrest. However, its efficacy in ischemic stroke remains unclear. We aimed to investigate whether carbon dioxide (CO₂) per-conditioning has neuroprotective effects in rat models with middle cerebral artery occlusion (MCAO). Rat models received intermittent inhalation of mixed gas during the MCAO period. After surgery, behavioral assessments, infarct size measurement, immunohistochemistry, and western blot analysis were performed. We found CO₂ per-conditioning reduced infarct size and neurological deficit. The number of 8-hydroxy-2-deoxyguanosine (8-OHdG) positive cells and matrix metalloproteinase 9 (MMP-9)/platelet derived growth factor receptor beta (PDGFRβ) double positive cells were significantly decreased after CO₂ per-conditioning. The expressions of tight junction protein and pericytes survival were preserved. This study underscores mild hypercapnia before reperfusion not only reduces neurologic deficit and infarct size, but also maintains the integrity of the blood-brain barrier and neurovascular unit, alongside mitigating oxidative stress in hyperacute stroke rat models. Therapeutic mild hypercapnia before reperfusion is promising and requires further clinical application.

Spreading depolarization (SD) develops after stroke and traumatic brain injury and may contribute to secondary brain damage. These diseases are often accompanied by intracranial hypertension, but little is known about the effects of intracranial pressure (ICP) on SD. Here, we study the effect of increased ICP on hemodynamic and metabolic response to SD in rats. SDs were triggered at different ICPs and cerebral perfusion pressures (CPP). The regional cerebral blood flow (rCBF), partial pressure of brain tissue oxygen (PbtO₂), cerebral extracellular glucose and lactate concentrations were recorded. Fluoro-Jade staining was used to quantify neuronal injury in cortex. At high ICP (50 mmHg) with low CPP (30 mmHg), rCBF and PbtO2 were monophasically decreased in contrast to a monophasically increased pattern under normal conditions. Neuronal death increased in both hemispheres but much more on the side where SDs were triggered. At high ICP (50 mmHg) with normal CPP (70 mmHg), CBF and metabolism during SD did not differ from baseline, and neuronal death did not increase even on the side of SD induction. These data suggest that maintaining CPP at 70 mmHg, even when the ICP is as high as 50 mmHg, preserves normal blood flow and metabolism during SD events and prevents neuronal degeneration.